Fully human IgG and IgM antibodies directed against the carcinoembryonic antigen (CEA) Gold 4 epitope and designed for radioimmunotherapy (RIT) of colorectal cancers

BACKGROUND: Human monoclonal antibodies (MAbs) are needed for colon cancer radioimmunotherapy (RIT) to allow for repeated injections. Carcinoembryonic antigen (CEA) being the reference antigen for immunotargeting of these tumors, we developed human anti-CEA MAbs. METHODS: XenoMouse(®)-G2 animals were immunized with CEA. Among all the antibodies produced, two of them, VG-IgG2κ and VG-IgM, were selected for characterization in vitro in comparison with the human-mouse chimeric anti-CEA MAb X4 using flow cytometry, surface plasmon resonance, and binding to radiolabeled soluble CEA and in vivo in human colon carcinoma LS174T bearing nude mice. RESULTS: Flow cytometry analysis demonstrated binding of MAbs on CEA-expressing cells without any binding on NCA-expressing human granulocytes. In a competitive binding assay using five reference MAbs, directed against the five Gold CEA epitopes, VG-IgG2κ and VG-IgM were shown to be directed against the Gold 4 epitope. The affinities of purified VG-IgG2κ and VG-IgM were determined to be 0.19 ± 0.06 × 10(8 )M(-1 )and 1.30 ± 0.06 × 10(8 )M(-1), respectively, as compared with 0.61 ± 0.05 × 10(8 )M(-1 )for the reference MAb X4. In a soluble phase assay, the binding capacities of VG-IgG2κ and VG-IgM to soluble CEA were clearly lower than that of the control chimeric MAb X4. A human MAb concentration of about 10(-7 )M was needed to precipitate approximatively 1 ng (125)I-rhCEA as compared with 10(-9 )M for MAb X4, suggesting a preferential binding of the human MAbs to solid phase CEA. In vivo, 24 h post-injection, (125)I-VG-IgG2κ demonstrated a high tumor uptake (25.4 ± 7.3%ID/g), close to that of (131)I-X4 (21.7 ± 7.2%ID/g). At 72 h post-injection, (125)I-VG-IgG2κ was still concentrated in the tumor (28.4 ± 11.0%ID/g) whereas the tumor concentration of (131)I-X4 was significantly reduced (12.5 ± 4.8%ID/g). At no time after injection was there any accumulation of the radiolabeled MAbs in normal tissues. A pertinent analysis of VG-IgM biodistribution was not possible in this mouse model in which IgM displays a very short half-life due to poly-Ig receptor expression in the liver. CONCLUSION: Our human anti-CEA IgG2κ is a promising candidate for radioimmunotherapy in intact form, as F(ab')(2 )fragments, or as a bispecific antibody

Evaluation of potential innovative positron-emitting radionuclides for PET applications

International audienceThe opportunities offered by the construction in Nantes (France) of a high energy (70 MeV) and high intensity (2 simultaneous 350 μA proton beams and one 30 μA alpha beam) cyclotron (ARRONAX) for radiochemistry and nuclear medicine research has prompted us to reinvestigate the production of several beta+ isotopes. Fluorine-18 is widely used in clinical routine practice for PET examination, but fails to achieve all the potential benefits of PET imaging for one major reason: its short half-life is not suited to the long kinetics of large molecules, e.g. antibodies, which may be used for diagnostics (immuno-PET) and radioimmunotherapy. Since PET cameras achieve better image quantification than SPECT cameras, beta+/beta- couples of the same element, which will follow the same metabolic pathways, could be used to monitor radionuclide distribution, and thus to obtain more precise dosimetry, especially in the field of radioimmunotherapy (RIT)

ARRONAX, a high-energy and high-intensity cyclotron for nuclear medicine

Purpose This study was aimed at establishing a list of radionuclides of interest for nuclear medicine that can be produced in a high-intensity and high-energy cyclotron. Methods We have considered both therapeutic and positron emission tomography radionuclides that can be produced using a high-energy and a high-intensity cyclotron such as ARRONAX, which will be operating in Nantes (France) by the end of 2008. Novel radionuclides or radionuclides of current limited availability have been selected according to the following criteria: emission of positrons, low-energy beta or alpha particles, stable or short half-life daughters, half-life between 3 h and 10 days or generator-produced, favourable dosimetry, production from stable isotopes with reasonable cross sections. Results Three radionuclides appear well suited to targeted radionuclide therapy using beta (67Cu, 47Sc) or alpha (211At) particles. Positron emitters allowing dosimetry studies prior to radionuclide therapy (64Cu, 124I, 44Sc), or that can be generator-produced (82Rb, 68Ga) or providing the opportunity of a new imaging modality (44Sc) are considered to have a great interest at short term whereas 86Y, 52Fe, 55Co, 76Br or 89Zr are considered to have a potential interest at middle term. Conclusions Several radionuclides not currently used in routine nuclear medicine or not available in sufficient amount for clinical research have been selected for future production. High-energy, high-intensity cyclotrons are necessary to produce some of the selected radionuclides and make possible future clinical developments in nuclear medicine. Associated with appropriate carriers, these radionuclides will respond to a maximum of unmet clinical needs

Nuclear medical imaging using β+γ\beta+\gamma coincidences from 44^{44}Sc radio-nuclide with liquid xenon as detection medium

International audienceWe report on a new nuclear medical imaging technique based on the measurement of the emitter location in the three dimensions with a few mm spatial resolution using β+γ emitters. Such measurement could be realized thanks to a new kind of radio-nuclides which emit a γ-ray quasi-simultaneously with the β+ decay. The most interesting radio-nuclide candidate, namely 44Sc, will be potentially produced at the Nantes cyclotron ARRONAX. The principle is to reconstruct the intersection of the classical line of response (obtained with a standard PET camera) with the direction cone defined by the third γ-ray. The emission angle measurement of this additional γ-ray involves the use of a Compton telescope for which a new generation of camera based on a liquid xenon (LXe) time projection chamber is considered. GEANT3 simulations of a large acceptance LXe Compton telescope combined with a commercial micro-PET (LSO crystals) have been performed and the obtained results will be presented. They demonstrate that a good image can be obtained from the accumulation of each three-dimensional measured position. A spatial resolution of 2.3 mm has been reached with an injected activity of 0.5 MBq for a 44Sc point source emitter